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PARIS (AFP) — The world's largest experiment using gene therapy to combat the AIDS virus has yielded "a major advance," demonstrating that the technique is both beneficial and safe, scientists said on Sunday. Data from an advanced phase of the test process confirms that the quest to use transplanted genes to roll back the human immunodeficiency virus (HIV) is valid, they said. Doctors led by Ronald Mitsuyasu of the University of California in Los Angeles recruited 74 HIV-infected volunteers for the experiment, whose results are reported online by the journal Nature Medicine.

Half the group were given blood stemcells that had been infiltrated by a crippled virus containing a key gene, while the other were given a harmless lookalike substance. The gene encodes something called an RNA enzyme, or ribozyme for short -- a small molecule that, like a spanner thrown into a machine, is intended to block HIV from replicating once it infects a cell. Stemcells are progenitor cells, which means that when they replicate, future generations of those cells will carry the same genetic code. The goal was to see whether these novel stemcells, by being shielded from HIV thanks to the ribozyme, would survive the body's immune defences and whether HIV, denied a haven for reproduction, would retreat. Forty-eight weeks after the so-called OZ1 experiment began, there was no statistical difference between those who had received the gene and those who were given the placebo.

But at the 100-week mark, there was encouraging news: in the gene group, the viral count was significally lower. And the count of CD4 cells -- immune cells that are depleted by HIV -- was higher. The stock of new blood cells, though, became rather depleted. Four weeks after they were introduced, a DNA test found the modified cells were present in 94 percent of participants in the OZ1 group, which fell to 12 percent by week 48 and to just seven percent at week 100.

None of the gene group experienced any adverse reaction to the therapy. The treatment "is safe and has efficacy, albeit modest," the study says. "It shows the potential of the gene therapy approach for the treatment of HIV and represents a major advance in the field... [it] can be developed as a conventional therapeutic product." Gene therapy arose in the latter years of the Nineties as a golden dawn in medical research. It conjured a vision whereby a gene, slotted into cells, would either correct a flawed gene that caused disease or, as in the case of the OZ1 trial, block progression of a pathogen. But the prospects suddenly darkened when an 18-year-old American, Jesse Gelsinger, tragically died in an experiment in 1999 to reverse a rare metabolic disorder. In several other incidents, gene-based treatments caused leukaemia.

Amid a tightening of regulatory oversight, gene therapy has only recently yielded what appears to be its first cures, reviving the immune systems of children with severe combined immunodeficiency, or SCID. In the field of HIV gene therapy, scientists are exploring more than half a dozen avenues for delivering genes to thwart the AIDS virus.

If HIV gene therapy works, doctors hope patients may be able to scrap, or at least reduce, their regimen of antiretroviral drugs. These powerful compounds can have toxic side effects, develop viral resistance and have to be taken for the rest of one's life.

In an interview with AFP, Mitsuyasu said this experiment was a Phase II trial in the long, three-phase process to test prototype treatments for safety and effectiveness. He said he would not put the technique to the final, third phase of the process. Instead, the team would learn from its experience, modify the technique and start again with tests on a smaller group of volunteers.

Mitsuyasu was upbeat. "I think it gives some hope to this approach being used in HIV and perhaps in other diseases as well, in cancer and congenital defects where we know that there is a gene that might be replaced or fixed," he said.

"It's a positive finding for the field, and should move the field forward."

Feb. 16, 2009 -- A one-time gene therapy that puts an anti- HIV RNA weapon into blood cells is safe and, in higher doses and stronger form, could make the body resist the AIDS virus, a clinical trial suggests.

This "major advance in the field" is the largest clinical trial ever to test genetically altered cells in humans, say UCLA researcher Ronald T. Mitsuyasu, MD, and colleagues.

"This study indicates that cell-delivered gene transfer is safe and biologically active in individuals with HIV and can be developed as a conventional therapeutic product," the researchers report in the Feb. 15 advance online issue of Nature Medicine.

The treatment calls for patients to get shots of a growth factor that stimulates growth of white blood cells. Then the cells are taken from their blood. Blood stem cells are separated out and put in cell culture dishes.

In the culture, the patients' own blood stem cells are infected with OZ1, a genetically engineered mouse virus that gives them an anti-HIV gene. This gene encodes an RNA molecule called a ribozyme, which specifically targets and inactivates HIV genes.

Once equipped with the anti-HIV gene, the blood stem cells are transfused back into the patient. The idea is for these stem cells to home in to the bone marrow and populate it with HIV-resistant T cells. As the older T cells die off or are killed by HIV, more and more of the body's T cells should be HIV resistant.

In this phase II clinical trial, 74 patients got infusions -- 38 with OZ1-equipped stem cells and 36 with inactive placebo infusions. All of the patients had HIV infection and had their infections under control with highly active antiretroviral (HAART) drug combinations.

What happened? First and foremost, nobody got hurt. There were no harmful side effects linked to the OZ1 gene therapy in the 100-week study. And there was no sign that HIV developed resistance to the anti-HIV ribozyme encoded in the gene therapy.

And even though doses were kept low, there were anti-HIV effects:

Throughout the 100-week trial, patients who received the OZ1 cells had higher numbers of CD4 T cells, the kind of white blood cell that HIV attacks and kills. When patients went off their anti-HIV drugs, those who received the gene therapy were able to postpone restarting treatment longer than those who received a placebo. During treatment interruptions, treated patients had higher CD4 T-cell counts and lower HIV viral load than placebo patients.

Now that researchers have shown this kind of gene therapy can work, future treatments will increase the dose, improve homing to the bone marrow, and carry an even more powerful anti-HIV gene. And in the future, patients would be treated before starting anti-HIV drugs.